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Central role for hydrogen peroxide in P2Y1 ADP receptor-mediated cellular responses in vascular endothelium
ADP activates a family of cell surface receptors that modulate signaling pathways in a broad range of cells. ADP receptor antagonists are widely used to treat cardiovascular disease states. These studies identify a critical role for the stable reactive oxygen species hydrogen peroxide (H2O2) in medi...
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| Published in: | Proceedings of the National Academy of Sciences - PNAS 2014-03, Vol.111 (9), p.3383-3388 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Kalwa, Hermann Sartoretto, Juliano L. Martinelli, Roberta Romero, Natalia Steinhorn, Benjamin S. Tao, Ming Ozaki, C. Keith Carman, Christopher V. Michel, Thomas |
| description | ADP activates a family of cell surface receptors that modulate signaling pathways in a broad range of cells. ADP receptor antagonists are widely used to treat cardiovascular disease states. These studies identify a critical role for the stable reactive oxygen species hydrogen peroxide (H2O2) in mediating cellular responses activated by the G protein-coupled P2Y1 receptor for ADP. We found that ADP-dependent phosphorylation of key endothelial signaling proteins—including endothelial nitric oxide synthase, AMP-activated protein kinase, and the actin-binding MARCKS protein— was blocked by preincubation with PEG-catalase, which degrades H2O2. ADP treatment promoted the H2O2-dependent phosphorylation of c-Abl, a nonreceptor tyrosine kinase that modulates the actin cytoskeleton. Cellular imaging experiments using fluorescence resonance energy transfer-based biosensors revealed that ADP-stimulated activation of the cytoskeleton-associated small GTPase Rac1 was independent of H2O2. However, Rac1-dependent activation of AMP-activated protein kinase, the signaling phospholipid phosphatidylinositol-(4, 5)-bisphosphate, and the c-Abl–interacting protein CrkII are mediated by H2O2. We transfected endothelial cells with differentially targeted HyPer2 H2O2 biosensors and found that ADP promoted a marked increase in H2O2 levels in the cytosol and caveolae, and a smaller increase in mitochondria. We performed a screen for P2Y1 receptor-mediated receptor tyrosine kinase transactivation and discovered that ADP transactivates Fms-like tyrosine kinase 3 (Flt3), a receptor tyrosine kinase expressed in these cells. Our observation that P2Y1 receptor-mediated responses involve Flt3 transactivation may identify a unique mechanism whereby cancer chemotherapy with receptor tyrosine kinase inhibitors promotes vascular dysfunction. Taken together, these findings establish a critical role for endogenous H2O2 in control of ADP-mediated signaling responses in the vascular wall. |
| doi_str_mv | 10.1073/pnas.1320854111 |
| format | article |
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Keith ; Carman, Christopher V. ; Michel, Thomas</creator><creatorcontrib>Kalwa, Hermann ; Sartoretto, Juliano L. ; Martinelli, Roberta ; Romero, Natalia ; Steinhorn, Benjamin S. ; Tao, Ming ; Ozaki, C. Keith ; Carman, Christopher V. ; Michel, Thomas</creatorcontrib><description>ADP activates a family of cell surface receptors that modulate signaling pathways in a broad range of cells. ADP receptor antagonists are widely used to treat cardiovascular disease states. These studies identify a critical role for the stable reactive oxygen species hydrogen peroxide (H2O2) in mediating cellular responses activated by the G protein-coupled P2Y1 receptor for ADP. We found that ADP-dependent phosphorylation of key endothelial signaling proteins—including endothelial nitric oxide synthase, AMP-activated protein kinase, and the actin-binding MARCKS protein— was blocked by preincubation with PEG-catalase, which degrades H2O2. ADP treatment promoted the H2O2-dependent phosphorylation of c-Abl, a nonreceptor tyrosine kinase that modulates the actin cytoskeleton. Cellular imaging experiments using fluorescence resonance energy transfer-based biosensors revealed that ADP-stimulated activation of the cytoskeleton-associated small GTPase Rac1 was independent of H2O2. However, Rac1-dependent activation of AMP-activated protein kinase, the signaling phospholipid phosphatidylinositol-(4, 5)-bisphosphate, and the c-Abl–interacting protein CrkII are mediated by H2O2. We transfected endothelial cells with differentially targeted HyPer2 H2O2 biosensors and found that ADP promoted a marked increase in H2O2 levels in the cytosol and caveolae, and a smaller increase in mitochondria. We performed a screen for P2Y1 receptor-mediated receptor tyrosine kinase transactivation and discovered that ADP transactivates Fms-like tyrosine kinase 3 (Flt3), a receptor tyrosine kinase expressed in these cells. Our observation that P2Y1 receptor-mediated responses involve Flt3 transactivation may identify a unique mechanism whereby cancer chemotherapy with receptor tyrosine kinase inhibitors promotes vascular dysfunction. Taken together, these findings establish a critical role for endogenous H2O2 in control of ADP-mediated signaling responses in the vascular wall.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1320854111</identifier><identifier>PMID: 24550450</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Adenosine Diphosphate - metabolism ; Animals ; Biological Sciences ; Biosensing techniques ; Cancer ; Cardiovascular disease ; Cattle ; Cell Line ; Chemotherapy ; Cultured cells ; Cytoskeleton ; Electric Impedance ; Endothelial cells ; Endothelial Cells - metabolism ; Endothelial Cells - physiology ; Enzyme Activation - genetics ; Enzyme Activation - physiology ; Fluorescence ; Fluorescence Resonance Energy Transfer ; fms-Like Tyrosine Kinase 3 - metabolism ; Humans ; Hydrogen peroxide ; Hydrogen Peroxide - metabolism ; Imaging ; Immunoblotting ; Microscopy, Fluorescence ; Modulated signal processing ; Oxidases ; Phosphorylation ; Physiological regulation ; Proteins ; Receptors ; Receptors, Purinergic P2Y1 - metabolism ; Signal Transduction - physiology</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2014-03, Vol.111 (9), p.3383-3388</ispartof><rights>copyright © 1993–2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Mar 4, 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c466t-ea785228287a6934aff5923704d5e73be5c2d0590de1cfa576aaec765cef51673</citedby><cites>FETCH-LOGICAL-c466t-ea785228287a6934aff5923704d5e73be5c2d0590de1cfa576aaec765cef51673</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/111/9.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/23770701$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/23770701$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,315,733,786,790,891,27957,27958,53827,53829,58593,58826</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24550450$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kalwa, Hermann</creatorcontrib><creatorcontrib>Sartoretto, Juliano L.</creatorcontrib><creatorcontrib>Martinelli, Roberta</creatorcontrib><creatorcontrib>Romero, Natalia</creatorcontrib><creatorcontrib>Steinhorn, Benjamin S.</creatorcontrib><creatorcontrib>Tao, Ming</creatorcontrib><creatorcontrib>Ozaki, C. Keith</creatorcontrib><creatorcontrib>Carman, Christopher V.</creatorcontrib><creatorcontrib>Michel, Thomas</creatorcontrib><title>Central role for hydrogen peroxide in P2Y1 ADP receptor-mediated cellular responses in vascular endothelium</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>ADP activates a family of cell surface receptors that modulate signaling pathways in a broad range of cells. ADP receptor antagonists are widely used to treat cardiovascular disease states. These studies identify a critical role for the stable reactive oxygen species hydrogen peroxide (H2O2) in mediating cellular responses activated by the G protein-coupled P2Y1 receptor for ADP. We found that ADP-dependent phosphorylation of key endothelial signaling proteins—including endothelial nitric oxide synthase, AMP-activated protein kinase, and the actin-binding MARCKS protein— was blocked by preincubation with PEG-catalase, which degrades H2O2. ADP treatment promoted the H2O2-dependent phosphorylation of c-Abl, a nonreceptor tyrosine kinase that modulates the actin cytoskeleton. Cellular imaging experiments using fluorescence resonance energy transfer-based biosensors revealed that ADP-stimulated activation of the cytoskeleton-associated small GTPase Rac1 was independent of H2O2. However, Rac1-dependent activation of AMP-activated protein kinase, the signaling phospholipid phosphatidylinositol-(4, 5)-bisphosphate, and the c-Abl–interacting protein CrkII are mediated by H2O2. We transfected endothelial cells with differentially targeted HyPer2 H2O2 biosensors and found that ADP promoted a marked increase in H2O2 levels in the cytosol and caveolae, and a smaller increase in mitochondria. We performed a screen for P2Y1 receptor-mediated receptor tyrosine kinase transactivation and discovered that ADP transactivates Fms-like tyrosine kinase 3 (Flt3), a receptor tyrosine kinase expressed in these cells. Our observation that P2Y1 receptor-mediated responses involve Flt3 transactivation may identify a unique mechanism whereby cancer chemotherapy with receptor tyrosine kinase inhibitors promotes vascular dysfunction. Taken together, these findings establish a critical role for endogenous H2O2 in control of ADP-mediated signaling responses in the vascular wall.</description><subject>Adenosine Diphosphate - metabolism</subject><subject>Animals</subject><subject>Biological Sciences</subject><subject>Biosensing techniques</subject><subject>Cancer</subject><subject>Cardiovascular disease</subject><subject>Cattle</subject><subject>Cell Line</subject><subject>Chemotherapy</subject><subject>Cultured cells</subject><subject>Cytoskeleton</subject><subject>Electric Impedance</subject><subject>Endothelial cells</subject><subject>Endothelial Cells - metabolism</subject><subject>Endothelial Cells - physiology</subject><subject>Enzyme Activation - genetics</subject><subject>Enzyme Activation - physiology</subject><subject>Fluorescence</subject><subject>Fluorescence Resonance Energy Transfer</subject><subject>fms-Like Tyrosine Kinase 3 - metabolism</subject><subject>Humans</subject><subject>Hydrogen peroxide</subject><subject>Hydrogen Peroxide - metabolism</subject><subject>Imaging</subject><subject>Immunoblotting</subject><subject>Microscopy, Fluorescence</subject><subject>Modulated signal processing</subject><subject>Oxidases</subject><subject>Phosphorylation</subject><subject>Physiological regulation</subject><subject>Proteins</subject><subject>Receptors</subject><subject>Receptors, Purinergic P2Y1 - metabolism</subject><subject>Signal Transduction - physiology</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><recordid>eNpVkc1v1DAQxS1ERbeFMyeQJc5pZ_wROxekatsCUiV6gAMny3Um3SzZONhJRf_7ZtmybU8jeX7vzbMeY-8RThCMPB16n09QCrBaIeIrtkCosChVBa_ZAkCYwiqhDtlRzmsAqLSFN-xQKK1BaViw30vqx-Q7nmJHvImJr-7rFG-p5wOl-Letibc9vxa_kJ-dX_NEgYYxpmJDdetHqnmgrps6n-ZVHmKfKW8Fdz6Hf6_U13FcUddOm7fsoPFdpneP85j9vLz4sfxaXH3_8m15dlUEVZZjQd5YLYQV1viykso3ja6ENKBqTUbekA6iBl1BTRgar03pPQVT6kCNxtLIY_Z55ztMN3PMsPuhG1K78eneRd-6l5u-XbnbeOdkpayQMBt8ejRI8c9EeXTrOKV-zuxQQ6mNFQZn6nRHhRRzTtTsLyC4bTtu2457amdWfHwebM__r-MZsFXu7RBd5aS0cgY-7IB1nkt4MpDGgAGUDxrzoLM</recordid><startdate>20140304</startdate><enddate>20140304</enddate><creator>Kalwa, Hermann</creator><creator>Sartoretto, Juliano L.</creator><creator>Martinelli, Roberta</creator><creator>Romero, Natalia</creator><creator>Steinhorn, Benjamin S.</creator><creator>Tao, Ming</creator><creator>Ozaki, C. 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Keith</au><au>Carman, Christopher V.</au><au>Michel, Thomas</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Central role for hydrogen peroxide in P2Y1 ADP receptor-mediated cellular responses in vascular endothelium</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2014-03-04</date><risdate>2014</risdate><volume>111</volume><issue>9</issue><spage>3383</spage><epage>3388</epage><pages>3383-3388</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><notes>Edited by Louis J. Ignarro, University of California, Los Angeles School of Medicine, Beverly Hills, CA, and approved January 23, 2014 (received for review November 6, 2013)</notes><notes>Author contributions: H.K., J.L.S., R.M., N.R., B.S.S., M.T., C.K.O., C.V.C., and T.M. designed research; H.K., J.L.S., R.M., N.R., B.S.S., M.T., and C.V.C. performed research; H.K., J.L.S., R.M., N.R., B.S.S., M.T., C.K.O., C.V.C., and T.M. contributed new reagents/analytic tools; H.K., J.L.S., R.M., N.R., B.S.S., C.K.O., C.V.C., and T.M. analyzed data; and H.K. and T.M. wrote the paper.</notes><abstract>ADP activates a family of cell surface receptors that modulate signaling pathways in a broad range of cells. ADP receptor antagonists are widely used to treat cardiovascular disease states. These studies identify a critical role for the stable reactive oxygen species hydrogen peroxide (H2O2) in mediating cellular responses activated by the G protein-coupled P2Y1 receptor for ADP. We found that ADP-dependent phosphorylation of key endothelial signaling proteins—including endothelial nitric oxide synthase, AMP-activated protein kinase, and the actin-binding MARCKS protein— was blocked by preincubation with PEG-catalase, which degrades H2O2. ADP treatment promoted the H2O2-dependent phosphorylation of c-Abl, a nonreceptor tyrosine kinase that modulates the actin cytoskeleton. Cellular imaging experiments using fluorescence resonance energy transfer-based biosensors revealed that ADP-stimulated activation of the cytoskeleton-associated small GTPase Rac1 was independent of H2O2. However, Rac1-dependent activation of AMP-activated protein kinase, the signaling phospholipid phosphatidylinositol-(4, 5)-bisphosphate, and the c-Abl–interacting protein CrkII are mediated by H2O2. We transfected endothelial cells with differentially targeted HyPer2 H2O2 biosensors and found that ADP promoted a marked increase in H2O2 levels in the cytosol and caveolae, and a smaller increase in mitochondria. We performed a screen for P2Y1 receptor-mediated receptor tyrosine kinase transactivation and discovered that ADP transactivates Fms-like tyrosine kinase 3 (Flt3), a receptor tyrosine kinase expressed in these cells. Our observation that P2Y1 receptor-mediated responses involve Flt3 transactivation may identify a unique mechanism whereby cancer chemotherapy with receptor tyrosine kinase inhibitors promotes vascular dysfunction. Taken together, these findings establish a critical role for endogenous H2O2 in control of ADP-mediated signaling responses in the vascular wall.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>24550450</pmid><doi>10.1073/pnas.1320854111</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adenosine Diphosphate - metabolism Animals Biological Sciences Biosensing techniques Cancer Cardiovascular disease Cattle Cell Line Chemotherapy Cultured cells Cytoskeleton Electric Impedance Endothelial cells Endothelial Cells - metabolism Endothelial Cells - physiology Enzyme Activation - genetics Enzyme Activation - physiology Fluorescence Fluorescence Resonance Energy Transfer fms-Like Tyrosine Kinase 3 - metabolism Humans Hydrogen peroxide Hydrogen Peroxide - metabolism Imaging Immunoblotting Microscopy, Fluorescence Modulated signal processing Oxidases Phosphorylation Physiological regulation Proteins Receptors Receptors, Purinergic P2Y1 - metabolism Signal Transduction - physiology |
| title | Central role for hydrogen peroxide in P2Y1 ADP receptor-mediated cellular responses in vascular endothelium |
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